Environmental eustress promotes liver regeneration through the sympathetic regulation of type 1 innate lymphoid cells to increase IL-22 in mice.

BACKGROUND AND AIMS: The liver has the unique ability of regeneration, which is extremely important for restoring homeostasis after liver injury. Although clinical observations have revealed an association between psychological stress and the liver, whether stress has a causal influence on the liver regeneration remains markedly less defined. APPROACH AND RESULTS: Rearing rodents in an enriched environment (EE) can induce eustress or positive psychological stress. Herein, EE-induced eustress was found to significantly enhance the ability of liver regeneration after partial hepatectomy or carbon tetrachloride-induced liver injury based on the more rapid restoration of liver/body weight ratio and the significantly increased number of proliferating hepatocytes in EE mice. Mechanistically, the cytokine array revealed that IL-22 was markedly increased in the regenerating liver in response to EE. Blockade of IL-22 signaling abrogated the enhanced liver regeneration induced by EE. Group 1 innate lymphoid cells (ILCs), including type 1 ILCs (ILC1s), have been identified as the major sources of IL-22 in the regenerating liver. EE housing led to a rapid accumulation of hepatic ILC1s after partial hepatectomy and the EE-induced enhancement of liver regeneration and elevation of IL-22 was nearly eliminated in ILC1-deficient Tbx21-/- mice. Chemical sympathectomy or blockade of ß-adrenergic signaling also abolished the effect of EE on ILC1s and attenuated the enhanced liver regeneration of EE-housed mice. CONCLUSION: The study findings support the brain-liver axis and suggest that environment-induced eustress promotes liver regeneration through the sympathetic nerve/ILC1/IL-22 axis.

Exposure to an enriched environment promotes the terminal maturation and proliferation of natural killer cells in mice.

The maturation of natural killer (NK) cells is critical for the acquisition of robust effector functions and the immune response to tumors. However, the influence of psychological stress on NK-cell maturation remains unknown. In this study, we investigated the alteration of NK-cell maturation in response to enriched environment (EE) exposure, which induced eustress, or positive stress, in mice. Analysis of markers representing distinct mature stages revealed that EE promoted the terminal maturation of NK cells both centrally in the bone marrow and peripherally in the spleen and blood. Additionally, EE increased CD27+ immature and intermediate-mature NK cell proliferation in the bone marrow. Furthermore, EE exposure brought about a similar promoting effect on NK-cell maturation in tumor-bearing mice. In tumor-bearing mice, EE substantially enhanced the proliferative potential of splenic CD27+ NK cells compared to those in the bone marrow. EE-housed mice displayed a tumor-resistant phenotype and an increased proportion of intratumoral NK cells, especially CD11b+ CD27- mature NK cells, while splenectomy abolished the tumor-retardant effect caused by EE and EE-induced NK-cell infiltration into tumors. Given that our previous study demonstrated an important role for NK cells in EE-induced tumor inhibition, the findings of this study further indicate that the enhanced maturation and proliferation of splenic NK cells may contribute to EE-induced tumor inhibition to some extent. Taken together, the results of this study suggest a positive modulating effect of environment-induced eustress on NK-cell maturation, with potential implications for understanding how eustress boosts NK-cell antitumor immunity.

Cadherin 13 Inhibits Pancreatic Cancer Progression and Epithelial-mesenchymal Transition by Wnt/ß-Catenin Signaling.

Cadherin 13 (CDH13) is an atypical cadherin that exerts tumor-suppressive effects on cancers derived from epithelial cells. Although the CDH13 promoter is frequently hypermethylated in pancreatic cancer (PC), the direct impact of CDH13 on PC is unknown. Accordingly, the expression of CDH13 in PC cell lines and paired PC tissues was examined by immunohistochemistry, quantitative real-time PCR and western blotting. Our findings showed that CDH13 was downregulated in PC tissues and cell lines. Moreover, cell proliferation, migration and invasion were detected by CCK-8 assay, transwell migration assay and transwell invasion assay, respectively. Xenograft tumor experiments were used to determine the biological function of CDH13 in vivo. As revealed by our data, CDH13 overexpression significantly inhibited the proliferation, migration and invasion of human PC cells in vitro. The inhibitory effect of CDH13 on PC was further confirmed in animal models. Mice subcutaneously or orthotopically transplanted with CDH13-overexpressing CFPAC-1 cells developed significantly smaller tumors with less liver metastases and mesenteric metastases than those of the control group. Next, transcriptomics and western blot analysis were used to identify the underlying mechanisms. Further molecular mechanism studies showed that CDH13 overexpression inhibited the activation of the Wnt/ß-catenin signaling pathway and regulated the expression of epithelial-mesenchymal transition (EMT)-related markers. Our results indicated that CDH13 displayed an inhibitory effect on PC and suggested that CDH13 might be a potential biomarker and a new therapeutic target for PC.

Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a malignant disease with a poor prognosis. One prominent aspect of PDAC that contributes to its aggressive behavior is its altered cellular metabolism. The aim of this study was to characterize the oncogenic effects of ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, in PDAC development and to assess its potential as a therapeutic target for PDAC. Experimental Design: The expression of UQCRC1 in human PDAC tissues and p48-Cre/p53Flox/WT/LSL-KrasG12D (KPC) mouse pancreatic intraepithelial neoplasias (PanINs) was determined by immunohistochemistry. The role of UQCRC1 in promoting PDAC growth was evaluated in vitro in PANC-1 and CFPAC-1 cells and in vivo in transplanted mouse models of PDAC. Extracellular flux and RNA-Seq analyses were applied to investigate the mechanism of UQCRC1 in the regulation of mitochondrial metabolism and PDAC cell growth. The therapeutic potential of UQCRC1 in PDAC was assessed by knockdown of UQCRC1 using an RNA interference approach. Results: UQCRC1 expression showed a gradual increase during the progression from PanIN stages to PDAC in KPC mice. Elevated expression of UQCRC1 was observed in 72.3% of PDAC cases and was correlated with poor prognosis of the disease. UQCRC1 promoted PDAC cell growth in both in vitro experiments and in vivo subcutaneous and orthotopic mouse models. UQCRC1 overexpression resulted in increased mitochondrial oxidative phosphorylation (OXPHOS) and ATP production. The overproduced ATP was released into the extracellular space via the pannexin 1 channel and then functioned as an autocrine or paracrine agent to promote cell proliferation through the ATP/P2Y2-RTK/AKT axis. UQCRC1 knockdown or ATP release blockage could effectively inhibit PDAC growth. Conclusion: UQCRC1 has a protumor function and may serve as a potential prognostic marker and therapeutic target for PDAC.

Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve-Dependent Regulation of NKG2D and CCR5.

Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment-induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1-/- mice, but was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK-cell-depleted mice, suggesting a predominant role of NK cells in enriched environment-induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment-induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of ß-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611-22. ©2017 AACR.